Saul B. Kadin

Inhibition of IgE-mediated N-acetylglucosaminidase and serotonin release from rat basophilic leukemia cells (RBL-2H3) by tenidap : a novel anti-inflammatory agent

Tenidap [(Z)-5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- indole-1-carboxamide] is a novel anti-inflammatory compound of the oxindole class that currently is undergoing clinical evaluation in man. Here we demonstrate that tenidap inhibits (IC50 = approximately 10 microM) IgE-mediated secretion of granule constituents from the rat mast cell tumor line RBL-2H3. The inhibitory effect is rapid in onset, readily reversible, and appears to be unique when compared to a representative selection of other acidic (carboxylic acids, pyrazoles and oxicams) nonsteroidal anti-inflammatory compounds.

Chapter 25. Antibodies as Drug Carriers and Toxicity Reversal Agents

Publisher Summary This chapter focuses on the application of tumor specific antibodies in transporting specific therapeutic agents to precise target sites and anti-drug antibodies intoxicity reversal. In addition to their other uses, antibodies have been used in numerous diagnostic and analytic operations. Antibodies have been used to carry drugs, toxins, enzymes, radioactivity, and boron to specific tissue sites, particularly in the treatment of cancer, where the employment of such therapeutic regimens is governed by severe constraints that arise from their generally cytotoxic nature. In efforts to maximize the therapeutic ratios of drugs, particularly those that have previously demonstrated promising anti-tumor activities as single agents, drug-antibody complexes have received the major share of attention. The most extensively studied drug-antibody complex is that derived from chlorambucil, cytotoxic, alkylating agent that reacts with numerous biologically important nucleophiles. The report that enzymes could be coupled to antibodies with resultant retention of both immunologic and enzymatic activities was instrumental in the development of enzyme–antibody, conjugates designed to demonstrate anti-tumor cytotoxic activities. The development of the radioimmunoassay method has led to routine elicitation of antibodies to drugs. The systematic utilization of antibodies to reverse the effects of drugs is of more recent occurrence. Recent advent of the monoclonal hybridoma technique has made the production of pure, monospecific antibodies in high titer possible that will have a profound impact on future research in this area. The employment of modern protein purification techniques, coupled with the use of the non-complement fixing, relatively non-immunogenic, and rapidly excreted fab antibody fragment, has led to the establishment of a viable method for reversing the toxicity of drugs.